Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Origin and Physiological Roles of Inflammation

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

Oxidative stress and diabetic complications

Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling For a wound to heal successfully, all four phases must occur in the proper sequence and time frame Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds

Factors Affecting Wound Healing

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion

Skin injury is a common occurrence and mechanical forces are known to significantly impact the biological processes of skin regeneration and wound healing. Immediately following the disruption of the skin, the process of wound healing begins, bringing together numerous cell types to collaborate in several sequential phases. These cells produce a multitude of molecules and initiate multiple signaling pathways that are associated with skin disorders and abnormal wound healing, including hypertrophic scars, keloids, and chronic wounds. Studies have shown that mechanical forces can alter the microenvironment of a healing wound, causing changes in cellular function, motility, and signaling. A better understanding of the mechanobiology of cells in the skin is essential in the development of efficacious therapeutics to reduce skin disorders, normalize abnormal wound healing, and minimize scar formation.

Mechanotransduction in Wound Healing and Fibrosis.

Endothelial progenitor cells: the promise of vascular stem cells for plastic surgery.

Significance: Chronic wounds are a prevalent and costly problem in the United States. Improved treatments are needed to heal these wounds and prevent serious complications such as infection and amputation. Recent Advances: In wound healing, as in other areas of medicine, technologies that have the potential to regenerate as opposed to repair tissue are gaining ground. These include customizable nanofiber matrices incorporating novel materials; a variety of autologous and allogeneic cell types at various stages of differentiation (e.g., pluripotent, terminally differentiated); peptides; proteins; small molecules; RNA inhibitors; and gene therapies. Critical Issues: Wound healing is a logical target for regenerative medicine due to the accessibility and structure of skin, the regenerative nature of healing, the lack of good limb salvage treatments, and the current use of cell therapies. However, more extensive knowledge of pathophysiologic targets is needed to inform regenerative strategies, and new technologies must demonstrate value in terms of outcomes and related health economic measures to achieve successful market access and penetration. Future Directions: Due to similarities in cell pathways and developmental mechanisms, regenerative technologies developed in one therapeutic area may be applicable to others. Approaches that proceed from human genomic or other big data sources to models are becoming increasingly common and will likely suggest novel therapeutic avenues. To fully capitalize on the advances in regenerative medicine, studies must demonstrate the value of new therapies in identified patient populations, and sponsors must work with regulatory agencies to develop appropriate dossiers supporting timely approval.

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Regenerative Medicine: Charting a New Course in Wound Healing

Introduction: Normal wound healing mechanisms can be overwhelmed in the setting of complex acute and chronic tissue injury. Biological therapies are designed to augment and/or restore the body's natural wound healing abilities. There are a variety of available and emerging technologies utilizing this approach that have demonstrated the ability to augment wound healing. Areas covered: In this review, the clinical data on launched and emerging biological therapies for wound healing applications are summarized. The methodologies discussed include biological skin equivalents, growth factors/small molecules and stem cell-based therapies. Expert opinion: While many products possess convincing clinical data demonstrating their efficacy in comparison to standard treatment options, more robust, controlled studies are needed to determine the relative value among established and emerging biological therapies. Future bioengineering and stem cell-based approaches are of particular interest due to the simultaneous corr...

Geoffrey C. Gurtner

Papers

Mechanotransduction in Wound Healing and Fibrosis.

Endothelial progenitor cells: the promise of vascular stem cells for plastic surgery.

Regenerative Medicine: Charting a New Course in Wound Healing

Biological therapies for the treatment of cutaneous wounds: Phase III and launched therapies

Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation.